Endometriosis is defined as the presence of endometrium-like tissue outside of the uterine cavity. It is one of the most common causes of infertility and chronic pelvic pain and affects 1 in 10 women in the reproductive age group. It is inherited in a polygenic manner with a complex and multifactorial etiology. Although existence of this disease has been known for over 100 years, our current knowledge of its pathogenesis, the pathophysiology of related infertility and its spontaneous evolution is limited. Several reasons contribute to our lack of knowledge, the most critical being the difficulty in carrying out objective long term studies in women. Therefore, we have developed an appropriate non-human primate to study the etiology of this disease. We propose that endometriosis develops in two distinct phases. Phase I is invasive and dependent on ovarian steroids. Phase II, which is the active phase of the disease, is characterized by endogenous estrogen biosynthesis. Using the baboon model for endometriosis we will; 1) explore the role of paracrine factors produced by the endometrial tissue itself in endometriosis; 2) determine the role of endocrine factors on the ectopic establishment of endometrial tissue; and 3) investigate the physiological consequences of endometriosis on reproduction. Specifically, in Specific Aim 1, we will use the in vivo model system to characterize changes in estrogen receptor and aromatase gene expression during disease progression. These changes will establish the role for estrogen to directly or indirectly regulate metalloproteinases (MMP-3 and MMP-7) and vascular endothelial growth factor (VEGF) to enable menstrual tissues to implant in an ectopic site. In Specific Aim 2 we will determine the role of ovarian steroids, particularly estradiol, in the establishment of endometriotic lesions. We propose to use three treatment modalities following introduction of menstrual effluent into the peritoneal cavity: a) suppression of ovarian function following menses with GnRH agonists; b) addition of low doses of exogenous progesterone during the follicular phases; c) ovariectomy and steroid replacement following menstruation. In Specific Aim 3 we will determine the effects of endometriotic lesions on uterine receptivity. Using a simulated pregnant baboon model we will determine if the hCG-induced, functional changes in both epithelial and stromal cells are affected in baboons with endometriosis during the period of uterine receptivity. In addition, we will determine if treatment with an aromatase inhibitor suppresses the disease and reverses the deleterious effects on endometriosis on uterine receptivity. These studies will provide significant information on the establishment and progression of endometriosis and its potential effects on fertility. These studies have direct relevance for the diagnosis and treatment of this disease in women.